This invention resides generally in the fields of N-heterocyclic and electrochemistry, and in a preferred aspect provides a convenient and commercially practicable electrochemical oxidation of pyridine bases to corresponding carboxylic acids such as niacin.
In this regard, pyridinecarboxylic acids are useful inter alia as chemical intermediates and corrosion inhibitors. Further, one such acid identified as 3-pyridinecarboxylic acid (also known by the names Vitamin B-3, nicotinic acid and niacin) has particular value as an essential vitamin. Its importance in the human diet, for example, led in the 1940's to niacin fortification of wheat flour and other consumer products. The adoption and continuation of this practice has generated steady demand for niacin and a concomitent driving force for improved methods to produce this and other pyridinecarboxylic acids. Moreover, recent reports that niacin may help reduce cholesterol levels in the blood have sparked an even greater demand for improved synthetic processes in this area.
As background respecting these processes, early oxidations of pyridine derivatives such as methylpyridines were conducted using chemical oxidizing agents and catalysts. More recent investigations have included these chemical methodologies in addition to attempts at electrochemical oxidations.
Accordingly, reports relating to chemical oxidizing agents dating back over a hundred years disclose forming niacin by partial oxidation of nicotine with nitric acid, potassium permanganate or potassium dichromate. See Woodward, Badgett and Kaufman, Ind. Eng. Chem., Vol. 36, No. 6, (1944) p. 544 and sources cited therein. Studies using these chemical oxidizing agents have continued, for instance, with potassium permanganate oxidations of alkylpyridine bases being reported by Black, Depp and Corson, J, Org. Chem., Vol. 14, 14 (1949); by Lovrecek, Radovi Jugoslav. Akad. Znanosti i Umjetnosti 296, 65-83 (1953); and by Plattner, Keller, and Boller, Helv. Chim. Acta. 37, 1379-92 (1954). These reactions have suffered, however, in that they have generally caused excessive oxidation and resultant ring degradation, particularly with polyalkylpyridines. Likewise, Bengtsson, Acta. Chem. Scand. 9, 832-36 (1955) reports nitric acid oxidations of pyridine homologs which has proven a more economic route, but nevertheless requires undesirably high temperatures and pressures which can cause decarboxylation or loss of carbon dioxide from the resulting product.
Other reported chemical methodologies have included oxidation of pyridine derivatives with ozone, ozonized oxygen or ozonized air [G. B. Patent No. 17,003], and also oxidation by action of sulfuric acid in the presence of a selenium compound. U.S. Pat. Nos. 2,449,906 and 2,513,009. Additionally, U.S. Pat. No. 2,513,251 reports oxidation of pyridine derivatives by reaction with nitrogen tetraoxide in a sulfuric acid medium.
Still other chemical routes to this end have included catalytic air oxidations of pyridine derivatives, [U.S. Pat. No. 2,437,938 and Kucharczyk and Zvakova, Collection Czech. Chem. Commun. 28, 55-60 (1963)], as well as oxidations using electro-generated superoxide ion. Sagae, Fujihira, Lund and Osa, Heterocycles. Vol. 13 (1979), p. 13. Additionally, Woodward, Badgett and Kaufman, Ind Eng. Chem., Vol. 36, No. 6, (1944), p. 544 reports catalytic oxidation of pyridine derivatives in sulfuric acid using mercuric sulfate and bismuth trinitrate catalysts (with moderate success), and selenium, selenium dioxide, and copper selenite catalysts (with greater success).
As noted above, another general area of study in this field has been that of electrochemical oxidation. This discipline had its nascence in 1932 when electrochemical oxidations of 2-methylpyridine and nicotine to 2-pyridinecarboxylic acid and nicotinic acid, respectively, were first reported. Yokoyama Bull. Chem. Soc. Japan 7, 69-72 (1932) and Yokoyama, ibid, 7 103-S (1932). These early electrochemical oxidations occurred in a sulfuric acid medium at a lead anode. Reports have since been made through the years of electrochemical oxidations of various pyridine derivatives with varying levels of success, but these oxidations have consistently occurred in moderate or better yields only in highly acidic mediums having substantial mineral acid components.
For example, the following sources report formation of the named pyridinecarboxylic acids upon electrochemical oxidation of pyridine derivatives in mediums containing sulfuric acid and at anodes of lead or lead-dioxide, or in fewer cases platinum: (1) Nicotinic acid from nicotine, Fichter and Stenzl, Helv. Chim. Acta. 19, 1171 (1936); (2) Nicotinic acid from 3-methylpyridine, Kruglikov and Khomyakov, Tr. Mosk. Khim.-Teknol Inst. 1961 (32), 194; (3) Quinolinic acid from quinoline, Yokoyama and Yamamoto, Bull Chem. Soc. Japan 18, 121 (1943); Khomyakov, Bakhchisaraits'yan, Tioshin, Kruglikov and Kazakova, Tr. Mosk. Khim.-Teknol. Inst. (32), 249 (1961); Khomyakov and Borkhi, Tr. Vses. Nauch.-Issled. Inst. Khim. Reakivov Osobo Chist. Khim. Veshchestv 29, 226 (1966); Khomyakov, Bzbanovskii and Borkhi, ibid. 29, 304 (1966); Borkhi and Khomyakov, Khim. Geterotsikl Soedin 1967 (1), 167; and Tsodikov, Borkhi, Brudz, Khomutov and Khomyakov, ibid. 1967 (1) 112; (4) Nicotinic acid from 3-methylpyridine, and quinolinic acid from quinoline, Kulka, J. Am. Chem. Soc. 68, 2472 (1946); U.S. Pat. No. 2,512,483; Khomyakov and Kruglikov, Trudy Moskov. Khim.-Teknol. Inst. im. D. I. Mendeleeva (25), 178 (1957); and Khomyakov, Kruglikov and Berezovskii, Zhur. Obshchei Khim. 28, 2898 (1958); (5) Quinolinic acid from sulfonated quinoline, U.S Pat. No. 2,453,701; (6) Isonicotinic acid from the methylol derivative of 4-picoline, Krugilkov and Khomyakov, Tr. Mosk Khim.-Teknol. Inst. 1961 (32), 201; (7) Lutidinic acid from 2,4-lutidine, Khomyakov, Kruglikov, and Kazakova, Tr. Mosk. Khim.-Teknol. Inst. 1961 (32), 189; (8) Monosubstituted pyridinedicarboxylic acids from monosubstituted quinolines, Cochran and Little, J. Org. Chem. 26, 808 (1961); (9) Isocinchomeronic acid from 2-methyl-5-ethylpyridine, Borkhi and Khomyakov, Izohret. Prom. Obraztsy, Tovarnye Znaki 43 (20), 38 (1966); and Borkhi, Khim. Geterotsikl Soedin 1970 (10), 1362 (1970); and (10) Isonicotinic acid from 4-ethylpyridine, Nankov and Yankov, Elektrokhimiya 7 ( 12), 1865 (1971).
In addition, electrolytic oxidations of 4-methylpyridine in 20% nitric acid and 20% sulfuric acid mediums at platinum and lead dioxide anodes are reported by Ito and Kawada, Ann. Rept. Takamine Lab. 5, 14 (1953), as are oxidations of 4-ethylpyridine in these two mediums at a platinum anode. These same two authors also report another experiment in which an extremely poor yield resulted from an electrolytic oxidation of 4-methylpyridine in an alkaline bath. Similarly, U.S. Pat. No. 4,750,978 reports low product yields resulting from electrolytic oxidations of 2-methyl-3-quinolinecarboxylic acid in 15% aqueous NaOH baths, and Ochiai and Okuda report very poor yields resulting from the electrolytic oxidation of 2-picoline in alkaline (10% yield) and neutral (10% yield) baths in J Pharm. Soc Japan, 70, 156 (1950).
Addressing generally these processes discussed above, both chemical and electrochemical, they present problems and inconveniences on a laboratory scale which are multiplied greatly in commercial scale reactions. Catalytic oxidations often require expensive catalysts and/or oxidizing agents and long reaction times, require the use of high temperatures and pressures, and present difficulties in processing and recovering reaction products. Moreover, in several of the chemical processes, ring degradation and accompanying product losses result from excessive oxidation.
The electrochemical processes, on the other hand, generally avoid use of expensive chemical catalysts and oxidants and thus hold greater promise in these respects for providing economical routes to pyridinecarboxylic acids. Nevertheless, commercial and technical development of economic electrochemical processes in this area has seriously lagged to date, with most reports being largely the result of qualitative study. The applicant's own earlier U.S. Pat. No. 4,482,439 discloses a commercially-viable electrochemical oxidation of pyridine bases performed in a flow cell having either an anion - or cation-selective ion-exchange membrane divider at a lead dioxide anode and in an aqueous medium comprising sulfuric acid in at least a 1:1 equivalent ratio with the pyridine base in solution. This flow cell process provides excellent yields and constitutes a significant improvement over the prior art at the time. As in the many other reported electro-oxidations achieving notable yields, however, this process too is performed in a medium containing a substantial mineral acid (sulfuric acid) component. This presents disadvantages in that effective recovery of the carboxylic acid product from such mediums requires pH neutralization which can particularly cumbersome and expensive on a commercial scale.
Further, simple workups of electrolysis products are essential in commercial settings as in many cases more than half of the total synthesis investment is devoted to this procedure. Auxilliary salts which serve as electrolytes but complicate the workup procedure can thus lead to pronounced increases in manufacturing costs. See generally, Techniques of Chemistry. (N. L. Weinberg and B. V. Tilak ed.), p. 279, John Wiley & Sons (1982). Accordingly, an electrochemical process which would allow one to eliminate or at least substantially reduce the use of such auxilliary salts would provide great advantage in commercial settings.
It is in light of this extensive background that the applicant began his work to discover a convenient and effective commercial process to satisfy the continuing and increasing demand for these carboxylic acids, including of particular interest niacin for the reasons stated above. By this work the applicant has now succeeded in providing with this invention a commercially and technically important electrochemical process for oxidizing pyridine and other N-heterocyclic compounds.